Back to resultsThe Effect of Liraglutide on Dietary Lipid Induced Insulin Resistance in Humans
Primary Purpose
Insulin Resistance
Status
Unknown status
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Liraglutide
Sugar Pill
Sponsored by
About this trial
This is an interventional basic science trial for Insulin Resistance focused on measuring insulin resistance, lipid metabolism, glucose metabolism, high fat diets
Eligibility Criteria
Inclusion Criteria:
- Age 40-75 years old
- Body mass index (BMI) from 22 to 35 kg/m2
- Normal glucose tolerance as determined by fasting blood glucose (< 100 mg/dl) and 75 gm glucose load (2 hr glucose <140 mg/dl)
- Fasting triglyceride levels ≥ 75 mg/dl and <500 mg/dl
Exclusion Criteria:
- Type 1 or 2 diabetes mellitus or a hemoglobin A1c value >6.5 mg/dl
- Any diabetes medications in the past month, thiazolidinedione medications in the prior 3 months or prior regular use of insulin
- Lactose intolerance or avoidance of dairy products
- Creatinine > 2.0 mg/dl or other laboratory evidence of active disease, including hepatic enzyme elevation (AST or ALT) > 2.5 x normal and anemia (Hct < 35)
- Known 'Nonalcoholic Fatty Liver Disease'
- Malabsorption of fat or other nutrients, severe lactose intolerance or other significant gastrointestinal or pancreatic problems (including history of acute or chronic pancreatitis).
- Recent history of nausea or vomiting
- Acute bacterial or viral illness or evidence of other active infection in the past 4 weeks
- Prior cardiovascular event, stable or unstable angina or other major illness in the past 6 months
- Current regular use of anti-inflammatory medications or antioxidants in excess of a standard daily multi-vitamin, including over- the-counter medications and high dose salicylates (> 1 gm/ day)
- Subjects receiving a lipid lowering medication must be on a stable dose for at least 6 weeks prior to participation.
- Personal or family history of medullary thyroid carcinoma or in patients with multiple endocrine neoplasia 2
- Ethanol consumption more than 4 oz day
- Pregnancy, or lack of appropriate contraceptive use in premenopausal women (extremely rare in our older predominately male population)
- Poorly controlled hypertension, systolic blood pressure (SBP) > 150 or diastolic blood pressure (DBP) > 90 on 2 or more occasions during screening visits. Subjects receiving blood pressure medication will be on a stable dosing for at least 6 weeks prior to participation.
- BMI <22 and >35 kg/m2
Sites / Locations
- Carl T. Hayden VA Medical Hospital
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Liraglutide
Sugar pill
Arm Description
Liraglutide titration up to 1.8 mg/d over approximately 3 weeks
matching placebo and titration
Outcomes
Primary Outcome Measures
Whole Body Insulin Sensitivity (insulin suppression test)
An insulin suppression test will be measured before and approximately 3 weeks after each treatment phase. Key time frames for assessing steady state plasma glucose will be between 150 and 180 minutes during the insulin suppression test
Secondary Outcome Measures
Postprandial lipid changes (area under the curve difference in triglyceride,total apolipoprotein B100, apolipoprotein B48, and apolipoprotein C3.
The major endpoints will be the area under the curve difference in triglyceride and free fatty acids between treatment arms on test day 1 and 2 following a standard meal. Other postprandial lipids will include total apolipoprotein B100, apolipoprotein B48, and apolipoprotein C3.
Postprandial changes in glucose metabolism (total and incremental area under the curve differences in glucose, insulin and glucagon)
total and incremental area under the curve differences in glucose, insulin and glucagon between treatment arms
Changes in adipose tissue insulin signaling pathway activation (compare insulin signaling pathway activity (e.g., Akt and insulin receptor phosphorylation)
Adipose tissue biopsy samples will be used to compare insulin signaling pathway activity (e.g., Akt and insulin receptor phosphorylation) in placebo and liraglutide treatment phases.
subcutaneous adipose tissue lipid intermediates (e.g., ceramide, diacylglycerol, acylcarnitine concentrations)
Adipose tissue biopsy samples will be used to compare lipid intermediates in placebo and liraglutide treatment phases.
skeletal muscle tissue lipid intermediates (e.g., ceramide, diacylglycerol, acylcarnitine concentrations)
skeletal muscle tissue samples will be used to compare lipid intermediates in placebo and liraglutide treatment phases.
Adipose tissue inflammation measures (e.g., interleukin (IL)-6, and -8, adiponectin, TNF-alpha, nuclear factor-kappa b, gene and protein expression)
Adipose tissue biopsy samples will be used to compare inflammation measures in placebo and liraglutide treatment phases.
Skeletal muscle inflammation measures (e.g., IL-6,8, TNF-alpha, nuclear factor-kappa b gene and protein expression)
skeletal muscle tissue samples will be used to compare inflammation measures in placebo and liraglutide treatment phases
Adipose tissue arteriole function (vasodilation measurement)
Adipose tissue biopsy samples will be used to isolate arterioles and measure ex vivo vascular function in placebo and liraglutide treatment phases.
Changes in skeletal muscle insulin signaling pathway
skeletal muscle biopsy samples will be used to compare insulin signaling pathway activity (e.g., Akt and insulin receptor phosphorylation) in placebo and liraglutide treatment phases.
Full Information
NCT ID
NCT02403284
First Posted
November 3, 2014
Last Updated
March 11, 2020
Sponsor
Phoenix VA Health Care System
Collaborators
Novo Nordisk A/S
1. Study Identification
Unique Protocol Identification Number
NCT02403284
Brief Title
The Effect of Liraglutide on Dietary Lipid Induced Insulin Resistance in Humans
Official Title
The Effect of Liraglutide on Dietary Lipid Induced Insulin Resistance in Humans
Study Type
Interventional
2. Study Status
Record Verification Date
March 2020
Overall Recruitment Status
Unknown status
Study Start Date
March 2013 (undefined)
Primary Completion Date
December 2020 (Anticipated)
Study Completion Date
May 2021 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Phoenix VA Health Care System
Collaborators
Novo Nordisk A/S
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
In this research study, investigators will test the effects of an approved medication for diabetes,Liraglutide, to reduce insulin resistance that develops from eating a diet high in saturated fats.
Detailed Description
The specific aim of this study is to determine the ability of subacute liraglutide administration to protect against dietary lipid induced peripheral insulin resistance in non-diabetic subjects who have normal glucose tolerance. Recent data from our laboratory and others suggest that high fat meals, enriched with saturated fatty acids (SFA) in particular, have a unique and profound ability to induce rapid (in ≤ 24 hr) and profound onset of insulin resistance in humans. This is presumably mediated in part through delivery of lipids and lipid products generated during postprandial lipolysis into non-adipose tissue. This unique model therefore provides an excellent platform to test agents for their ability to inhibit dietary induced insulin resistance. As we and others have demonstrated the ability of GLP-1 receptor agonists to markedly suppress postprandial lipid elevations and to modify lipid metabolism, we hypothesize that liraglutide may be an effective agent to inhibit development of dietary induced insulin resistance.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Insulin Resistance
Keywords
insulin resistance, lipid metabolism, glucose metabolism, high fat diets
7. Study Design
Primary Purpose
Basic Science
Study Phase
Phase 4
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
35 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Liraglutide
Arm Type
Experimental
Arm Description
Liraglutide titration up to 1.8 mg/d over approximately 3 weeks
Arm Title
Sugar pill
Arm Type
Placebo Comparator
Arm Description
matching placebo and titration
Intervention Type
Drug
Intervention Name(s)
Liraglutide
Other Intervention Name(s)
Victoza
Intervention Description
Subcutaneous injection by patient
Intervention Type
Drug
Intervention Name(s)
Sugar Pill
Other Intervention Name(s)
Placebo
Intervention Description
Subcutaneous injection daily
Primary Outcome Measure Information:
Title
Whole Body Insulin Sensitivity (insulin suppression test)
Description
An insulin suppression test will be measured before and approximately 3 weeks after each treatment phase. Key time frames for assessing steady state plasma glucose will be between 150 and 180 minutes during the insulin suppression test
Time Frame
3 weeks
Secondary Outcome Measure Information:
Title
Postprandial lipid changes (area under the curve difference in triglyceride,total apolipoprotein B100, apolipoprotein B48, and apolipoprotein C3.
Description
The major endpoints will be the area under the curve difference in triglyceride and free fatty acids between treatment arms on test day 1 and 2 following a standard meal. Other postprandial lipids will include total apolipoprotein B100, apolipoprotein B48, and apolipoprotein C3.
Time Frame
3 weeks
Title
Postprandial changes in glucose metabolism (total and incremental area under the curve differences in glucose, insulin and glucagon)
Description
total and incremental area under the curve differences in glucose, insulin and glucagon between treatment arms
Time Frame
3 weeks
Title
Changes in adipose tissue insulin signaling pathway activation (compare insulin signaling pathway activity (e.g., Akt and insulin receptor phosphorylation)
Description
Adipose tissue biopsy samples will be used to compare insulin signaling pathway activity (e.g., Akt and insulin receptor phosphorylation) in placebo and liraglutide treatment phases.
Time Frame
3 weeks
Title
subcutaneous adipose tissue lipid intermediates (e.g., ceramide, diacylglycerol, acylcarnitine concentrations)
Description
Adipose tissue biopsy samples will be used to compare lipid intermediates in placebo and liraglutide treatment phases.
Time Frame
3 weeks
Title
skeletal muscle tissue lipid intermediates (e.g., ceramide, diacylglycerol, acylcarnitine concentrations)
Description
skeletal muscle tissue samples will be used to compare lipid intermediates in placebo and liraglutide treatment phases.
Time Frame
3 weeks
Title
Adipose tissue inflammation measures (e.g., interleukin (IL)-6, and -8, adiponectin, TNF-alpha, nuclear factor-kappa b, gene and protein expression)
Description
Adipose tissue biopsy samples will be used to compare inflammation measures in placebo and liraglutide treatment phases.
Time Frame
3 weeks
Title
Skeletal muscle inflammation measures (e.g., IL-6,8, TNF-alpha, nuclear factor-kappa b gene and protein expression)
Description
skeletal muscle tissue samples will be used to compare inflammation measures in placebo and liraglutide treatment phases
Time Frame
3 weeks
Title
Adipose tissue arteriole function (vasodilation measurement)
Description
Adipose tissue biopsy samples will be used to isolate arterioles and measure ex vivo vascular function in placebo and liraglutide treatment phases.
Time Frame
3 weeks
Title
Changes in skeletal muscle insulin signaling pathway
Description
skeletal muscle biopsy samples will be used to compare insulin signaling pathway activity (e.g., Akt and insulin receptor phosphorylation) in placebo and liraglutide treatment phases.
Time Frame
3 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
40 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Age 40-75 years old
Body mass index (BMI) from 22 to 35 kg/m2
Normal glucose tolerance as determined by fasting blood glucose (< 100 mg/dl) and 75 gm glucose load (2 hr glucose <140 mg/dl)
Fasting triglyceride levels ≥ 75 mg/dl and <500 mg/dl
Exclusion Criteria:
Type 1 or 2 diabetes mellitus or a hemoglobin A1c value >6.5 mg/dl
Any diabetes medications in the past month, thiazolidinedione medications in the prior 3 months or prior regular use of insulin
Lactose intolerance or avoidance of dairy products
Creatinine > 2.0 mg/dl or other laboratory evidence of active disease, including hepatic enzyme elevation (AST or ALT) > 2.5 x normal and anemia (Hct < 35)
Known 'Nonalcoholic Fatty Liver Disease'
Malabsorption of fat or other nutrients, severe lactose intolerance or other significant gastrointestinal or pancreatic problems (including history of acute or chronic pancreatitis).
Recent history of nausea or vomiting
Acute bacterial or viral illness or evidence of other active infection in the past 4 weeks
Prior cardiovascular event, stable or unstable angina or other major illness in the past 6 months
Current regular use of anti-inflammatory medications or antioxidants in excess of a standard daily multi-vitamin, including over- the-counter medications and high dose salicylates (> 1 gm/ day)
Subjects receiving a lipid lowering medication must be on a stable dose for at least 6 weeks prior to participation.
Personal or family history of medullary thyroid carcinoma or in patients with multiple endocrine neoplasia 2
Ethanol consumption more than 4 oz day
Pregnancy, or lack of appropriate contraceptive use in premenopausal women (extremely rare in our older predominately male population)
Poorly controlled hypertension, systolic blood pressure (SBP) > 150 or diastolic blood pressure (DBP) > 90 on 2 or more occasions during screening visits. Subjects receiving blood pressure medication will be on a stable dosing for at least 6 weeks prior to participation.
BMI <22 and >35 kg/m2
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Peter D Reaven, MD
Organizational Affiliation
Carl T. Hayden Medical Research Foundation
Official's Role
Principal Investigator
Facility Information:
Facility Name
Carl T. Hayden VA Medical Hospital
City
Phoenix
State/Province
Arizona
ZIP/Postal Code
85012
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
No
IPD Sharing Plan Description
Subject to VA regulation.
Learn more about this trial
The Effect of Liraglutide on Dietary Lipid Induced Insulin Resistance in Humans
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